Constitutive activation of the kinase cascade involving RAS, RAF, MEK and ERK is common to human cancers, and mutations of KRAS and BRAF are mutually exclusive and serve as alternatives to activate the RAS/RAF/ERK signaling pathway. RAS mutations are known to occur in prostate adenocarcinomas, but little is known about BRAF mutations in these tumors. In the present study, BRAF and KRAS mutations were characterized in 206 prostate adenocarcinomas by enhanced PCR-RFLP and direct sequencing. The identified KRAS and BRAF mutations were then analyzed with respect to preoperative serum PSA levels, Gleason scores and tumor stages. Mutations in codon 600 of BRAF were identified in 21 (10.2%) of 206 prostate adenocarcinomas. KRAS mutations in codons 12 or 13 were found in 15 (7.3%) of 206 prostate adenocarcinomas. However, no tumor specimen contained both BRAF and KRAS mutations. Prostate adenocarcinomas with a BRAF mutation tended to show higher preoperative serum PSA levels, Gleason scores and tumor stages than prostate adenocarcinomas with a KRAS mutation. The results obtained show that BRAF mutations are as uncommon as KRAS mutations in prostate adenocarcinoma. Although BRAF and KRAS are members of the same RAS/ERK signaling pathway, prostate adenocarcinomas with a BRAF mutation showed clinicopathologic features that differed from those of prostate adenocarcinoma with a KRAS mutation. ' 2006 Wiley-Liss, Inc.

Background : Genetic polymorphism of methylenetetrahydrofolate reductase (MTHFR), in association with the influence of MTHFR upon DNA methylation, may cause differences of the methylation profile of cancer. Thus, we investigated the relationship between the methylation status of prostate adenocarcinoma and the genetic polymorphism of MTHFR. Methods : We examined 179 cases of prostate adenocarcinoma for determining the genotypes of MTHFR 677 and 1298, the methylation status of 16 CpG island loci and the methylation levels of the LINE-1 and Alu repeats with using polymerase chain reaction/restriction fragment length polymorphism, methylation-specific polymerase chain reaction and combined bisulphite restriction analysis, respectively. Results : There was a higher proportion of the CT genotype of MTHFR 677 in the prostate adenocarcinoma than that in the normal control. The TT genotype of MTHFR 677 showed the highest frequency of methylation in six out of nine major CpG island loci, and these were which were frequently hypermethylated in prostate adenocarcinoma. The CT type showed the lowest methylation levels of LINE-1 and Alu among the MTHFR 677 genotypes. Interestingly, the CC type of MTHFR 1298 demonstrated favorable prognostic factors. Conclusions : Our study is the first to examine the methylation profile of prostate adenocarcinoma according to the MTHFR genotypes. The differences of the cancer risk, the genomic hypomethylation and the prognosis between the MTHFR genotypes in prostate adenocarcinoma should be further explored.

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